The PGI2 Analog Cicaprost Inhibits IL-33-Induced Th2 Responses, IL-2 Production, and CD25 Expression in Mouse CD4+ T
Weisong Zhou1, Jian Zhang2, Shinji Toki2
1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and weisong.zhou@vanderbilt.edu.
IL-33 has pleiotropic functions in immune responses and promotes the development of allergic diseases and asthma. IL-33 induces Th2 differentiation and enhances type 2 cytokine production by CD4+ T cells. However, the regulation of IL-33-driven type 2 cytokine responses is not fully defined. In this study, we investigated the effect of PGI2, a lipid mediator formed in the cyclooxygenase pathway of arachidonic acid metabolism, on naive CD4+ T cell activation, proliferation, and differentiation by IL-33. Using wild-type and PGI2 receptor (IP) knockout mice, we found that the PGI2 analog cicaprost dose-dependently inhibited IL-33-driven IL-4, IL-5, and IL-13 production by CD4+ T cells in an IP-specific manner. In addition, cicaprost inhibited IL-33-driven IL-2 production and CD25 expression by CD4+ T cells. Furthermore, IP knockout mice had increased IL-5 and IL-13 responses of CD4+ T cells to Alternaria sensitization and challenge in mouse lungs. Because IL-33 is critical for Alternaria-induced type 2 responses, these data suggest that PGI2 not only inhibits IL-33-stimulated CD4+ Th2 cell responses in vitro but also suppresses IL-33-induced Th2 responses caused by protease-containing allergens in vivo.
IL-33 has pleiotropic functions in immune responses and promotes the development of allergic diseases and asthma. IL-33 induces Th2 differentiation and enhances type 2 cytokine production by CD4+ T cells. However, the regulation of IL-33-driven type 2 cytokine responses is not fully defined. In this study, we investigated the effect of PGI2, a lipid mediator formed in the cyclooxygenase pathway of arachidonic acid metabolism, on naive CD4+ T cell activation, proliferation, and differentiation by IL-33. Using wild-type and PGI2 receptor (IP) knockout mice, we found that the PGI2 analog cicaprost dose-dependently inhibited IL-33-driven IL-4, IL-5, and IL-13 production by CD4+ T cells in an IP-specific manner. In addition, cicaprost inhibited IL-33-driven IL-2 production and CD25 expression by CD4+ T cells. Furthermore, IP knockout mice had increased IL-5 and IL-13 responses of CD4+ T cells to Alternaria sensitization and challenge in mouse lungs. Because IL-33 is critical for Alternaria-induced type 2 responses, these data suggest that PGI2 not only inhibits IL-33-stimulated CD4+ Th2 cell responses in vitro but also suppresses IL-33-induced Th2 responses caused by protease-containing allergens in vivo.
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